Persistent pain and stress activate pain-inhibitory orexin pathways

Abstract

Orexins are synthesized by neurons in the hypothalamus and contribute to multiple physiological functions. Orexin fibers innervate many regions of the CNS, which include areas involved in descending control of pain. We examined the role orexins may play in endogenous modulation of pain transmission using prepro-orexin (precursor of orexin A and B) knockout mice. Baseline pain thresholds of knockout and wild type mice were not different. Knockout mice presented greater degree of hyperalgesia induced by peripheral inflammation and less stress-induced analgesia than wild type mice. Double staining of orexin and c-Fos in wild type mice revealed activation of orexin neurons under both conditions. These results suggest that persistent pain and stress activate orexin neurons, which act to inhibit pain transmission.

Hypocretin/orexin and nociceptin/orphanin FQ coordinately regulate analgesia in a mouse model of stress-induced analgesia

“…Using the conventional hot-plate and tail-flick tests, the thermal pain threshold did not differ between these 2 genotypes in either test (Supplemental Figure 1, C and D), consistent with previous observations in prepro-hcrt KO mice (12).…”

“…Defects in this system, either presynaptically or postsynaptically, result in the sleep disorder narcolepsy in both humans (29,30) and animals (25,(31)(32)(33). Converging lines of evidence also indicate roles for the Hcrt system in energy metabolism (21,25), cardiovascular control, reproductive and stress hormone secretion (34), reward and addiction (6,(35)(36)(37), and modulation of pain transmission by activating inhibitory pathways (12).…”

“…However, the Hcrt system has also been implicated in nociception, the stress response, and SIA. The Hcrt-1 peptide is analgesic (8)(9)(10), CRF excites Hcrt cells through the CRF receptor 1 (11), and SIA is reduced in Hcrtnull mutant mice (12).…”

“…To determine a functional role in vivo for a N/OFQ-Hcrt interaction, we investigated a behavior for which these 2 neuropeptides have been demonstrated to exhibit inverse actions: SIA. Previous studies had identified the Hcrt system as part of the CRF-mediated stress response (11) and showed that SIA is reduced in prepro-hcrt KO mice (12). To confirm the involvement of Hcrt in SIA, we used orexin/ataxin-3 mice, a transgenic strain in which the Hcrt cells degenerate postnatally and are completely lost by adulthood (25).…”

Stress-Induced Analgesia

“…Moreoever, when oxytocin, a neurohormone synthesized in the hypothalamus during the stress response, was lacking in mice, SIA induced by a cold-water swim and restraint for 30 minutes was attenuated (Robinson et al, 2002). Mice with a genetic disruption to orexin, which is also synthesized in the hypothalamus and plays a role in the transmission of pain, displayed a significant attenuation of SIA compared to wild-type mice (Watanabe et al, 2005). The hypothalamic hormone vasopressin was not initially believed to play a role in SIA when an intraperitoneal injection of hypertonic saline was used as a stressor (Wright and Lincoln, 1985); however, a later study concluded that vasopressin mediated SIA with a food restriction stressor (Wideman et al, 1996).…”